Preparation method of silodosin intermediate

A technology of silodosin and intermediates, applied in the field of pharmaceutical synthesis, can solve the problems of compound IX yield reduction, impact on compound XII yield, low selectivity of hydroformylation reaction, etc., and achieve the effect of improving yield

Active Publication Date: 2019-02-05
FUYANG XINYIHUA MATERIAL TECH
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Problems solved by technology

[0003] Structural formula such as The compound is the key intermediate for the preparation of silodosin, such as figure 1 As shown, in the existing synthetic process of the key intermediate of silodosin, compound X is usually reduced to obtain compound XI, and then compound XI is used for hydroformylation to obtain compound XII, but in the process of hydroformylation of compound XI Because there are many reaction sites that can be hydroformylated on the benzene ring, the reaction selectivity of the hydroformylation reaction is low, which affects the yield of compound XII, and then leads to a corresponding decrease in the yield of compound IX

Method used

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  • Preparation method of silodosin intermediate
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  • Preparation method of silodosin intermediate

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preparation example Construction

[0055] see figure 2 , the preparation method of silodosin intermediate provided in the embodiment of the present invention comprises:

[0056] S1: chiral-induced reductive amination of α-substituted acetonides to obtain initial intermediates; wherein,

[0057] The structural formula of α-substituted acetonides is:

[0058]

[0059] The structural formula of the initial intermediate is:

[0060]

[0061] S2: carry out amino protection to the initial intermediate to obtain an amino-protected intermediate; wherein, the structural formula of the amino-protected intermediate is:

[0062]

[0063] S3: hydroformylation of the amino-protected intermediate to obtain an hydroformylation intermediate; wherein,

[0064] The structural formula of the hydroformylation intermediate is:

[0065]

[0066] S4: oximation of the hydroformylation intermediate to obtain the oximation intermediate; wherein,

[0067] The structural formula of the oximation intermediate is:

[0068]...

Embodiment 1

[0134] The present embodiment provides a kind of preparation method of silodosin intermediate, comprising:

[0135] In the first step, the α-substituted acetonide was dissolved in tetrahydrofuran under hydrogen to make an initial solution, and then platinum oxide and R-phenylethylamine were added to it, and the above substances were stirred at room temperature for chiral-induced reduction Amination reaction, monitor the reductive amination reaction progress by thin-layer chromatography after 8 hours; Wherein, the mass ratio of α-substituted acetonide and platinum oxide is 1:0.1%, the molar ratio of α-substituted acetonide and R-phenylethylamine The ratio is 1:1.2;

[0136] When the reductive amination reaction reaches the end of the reaction, the platinum black obtained by the platinum oxidation reaction is recovered by filtration, the solvent tetrahydrofuran is recovered by rotary evaporation, and then ethyl acetate and hydrochloric acid are added to the residue to extract th...

Embodiment 2

[0162] The present embodiment provides a preparation method of a silodosin intermediate, comprising:

[0163] In the first step, the α-substituted acetone compound was dissolved in tetrahydrofuran to make the initial solution, then R-naphthaleneethylamine and sodium borohydride were added to it, and the above substances were stirred at room temperature to carry out reductive amination reaction, after 8 hours The progress of the reductive amination reaction was monitored by thin-layer chromatography; wherein, the molar ratio of α-substituted acetone to sodium borohydride was 1:1.80, and the molar ratio of α-substituted acetone to R-naphthylethylamine was 1:1.12;

[0164] When the reductive amination reaction reaches the reaction end point, the platinum black obtained by the platinum oxide reaction is filtered and recovered, the solvent tetrahydrofuran is recovered by rotary evaporation, and then ethyl acetate and hydrochloric acid are sequentially added to the residue to extract...

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Abstract

The invention discloses a preparation method of a silodosin intermediate and relates to the technical field of medical synthesis, aiming at solving the problem in an existing preparation method that the yield of the silodosin intermediate is low. The preparation method of the silodosin intermediate comprises the following steps: carrying out chirally-induced reductive amination on an alpha-substituted acetone compound to obtain an initial intermediate; carrying out amino protection on the initial intermediate to obtain an amino protected intermediate; carrying out hydroformylation on the aminoprotected intermediate to obtain a hydroformylated intermediate; carrying out oximation on the hydroformylated intermediate to obtain an oximated intermediate; carrying out cyaniding on the oximatedintermediate to obtain a cyanated intermediate; carrying out amino deprotection on the cyanated intermediate to obtain free alkali of the silodosin intermediate; carrying out salt forming treatment onthe free alkali of the silodosin intermediate to obtain the silodosin intermediate. The preparation method of the silodosin intermediate, provided by the invention, is used for preparing silodosin.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a preparation method of a silodosin intermediate. Background technique [0002] Silodosin is an α1-adrenoceptor antagonist developed by Kissei Pharmaceuticals for the treatment of benign prostatic hyperplasia. It is used to treat dysuria caused by benign prostatic hyperplasia. [0003] structure such as The compounds are key intermediates in the preparation of silodosin, such as figure 1 As shown, in the existing synthesis process of the key intermediate of silodosin, compound XI is usually obtained by reducing compound X, and then compound XII is obtained by hydroformylation of compound XI, but in the hydroformylation process of compound XI Because there are multiple reaction sites for hydroformylation on the benzene ring, the reaction selectivity of the hydroformylation reaction is low, which affects the yield of compound XII, which in turn leads to a corres...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08C07C59/255C07C51/41
CPCC07B2200/07C07D209/08
Inventor 孙睿尹强曹晶
Owner FUYANG XINYIHUA MATERIAL TECH
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